Nuclear cGAS suppresses DNA repair and promotes tumorigenesis
Nuclear cGAS suppresses DNA repair and promotes tumorigenesis
复制标题
核 cGAS 抑制 DNA 修复并促进肿瘤发生。
DOI：
10.1038/s41586-018-0629-6
复制
发表时间：
2018-11-01
期刊：
影响因子：
64.8
通讯作者：
Ge, Baoxue
中科院分区：
文献类型：
--
作者：
Liu, Haipeng;Zhang, Haiping;Ge, Baoxue
通过同源重组精确修复DNA双链断裂可保持基因组完整性并抑制肿瘤发生。环GMP-AMP合酶（cGAS）是一种细胞溶质DNA传感器，通过启动STING-IRF 3-I型IFN信号级联激活先天免疫（1，2）。cGAS对破裂微核的识别将基因组不稳定性与先天免疫应答联系起来（3，4），但cGAS在DNA修复中的潜在参与仍然未知。在这里，我们证明了cGAS抑制小鼠和人类模型中的同源重组。DNA损伤以依赖于importin-alpha的方式诱导cGAS的核转位，并且cGAS在酪氨酸215处的磷酸化-由B淋巴酪氨酸激酶介导-促进cGAS的胞质保留。在细胞核中，cGAS被募集到双链断裂处，并通过聚（ADP-核糖）与PARP 1相互作用。cGAS-PARP 1相互作用阻碍PARP 1-Timeless复合物的形成，从而抑制同源重组。我们表明cGAS的敲低抑制了DNA损伤并抑制了体外和体内肿瘤生长。我们得出结论，核cGAS抑制同源重组介导的修复并促进肿瘤生长，因此cGAS代表了癌症预防和治疗的潜在靶点。
Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade(1,2). Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response(3,4), but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-alpha, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS- PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.